ABSTRACT: Studies on the mechanism of action of drugs which alter the excitability of the CNS have contributed enormously not only to our understanding of CNS synaptic transmission but also to the rational development of therapeutic agents. My particular interests have centered on the mechanism of action of barbiturates in the CNS. It is well established that barbiturates depress excitatory synaptic transmission, but the relative importance of actions on transmitter release and postsynaptic sensitivity remains debatable. It is also known that barbiturates interact with gamma-aminobutyric acid (GABA) mediated transmission in a number of intriguing ways. For instance, barbiturates dramatically prolong pre- and postsynaptic inhibition and activate GABA receptors. The goals of the present proposal are to determine, 1) the relative importance of GABA pathways in the action of barbiturates, 2) the mechanisms involved in the interaction of barbiturates with GABA pathways at the cellular level, 3) the site of action of the depression of excitatory synaptic transmission. A number of well suited preparations will be used. For the first goal the action of convulsant barbiturates will be compared to the action of depressant barbiturates on the isolated spinal cord. The action of pentobarbital on postsynaptic inhibition will be analyzed in the crustacean stretch receptor. The effect of pentobarbital on excitatory synaptic transmission in the superior cervical ganglion will be detemined by examining quantal transmission. The proposed study thus promises to further our understanding of the physiological processes involved in synaptic transmission as well as to elucidate the basic mechanisms underlying the hypnotic properties of the clinically important barbiturates.